The hepatitis B virus (HBV), which belongs to the hepadnavirus family, is a causative agent of acute and chronic hepatitis. HBV infections are the world's ninth leading cause of death. HBV infection often leads to acute hepatitis and liver damage, and causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive form of the disease in which massive sections of the liver are destroyed. Many patients recover from acute viral hepatitis, but in certain other patients, especially young children, viral infection persists for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Chronic persistent hepatitis can cause fatigue, liver damage, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
HBV infection is a serious problem among the homo- and heterosexual population, intravenous drug users, organ transplant recipients, and blood transfusion patients. New infection with HBV can be prevented by vaccination. However, the present vaccination is not effective for the approximately 350 million chronic carriers worldwide. It has been observed that suppression or eradication of the replication of HBV in the liver leads to improved liver pathology and decreased progression to liver cirrhosis and hepatocellular carcinoma.
One of the current therapies approved in the United States for treating chronic hepatitis B infection is alpha interferon, which is far from ideal. According to the American Liver Foundation and the International Hepatitis Foundation, patients with conditions such as advanced hepatitis, HIV co-infection, drug abuse or others are not eligible for this treatment, resulting in less than 50% of chronic carriers obtaining this therapy. Of these patients, only about 40% respond to the treatment. Many of these patients also relapse after treatment is stopped, and only about 30% of the patients show a long term benefit. Viral disappearance is only seen in about 10-20% of the treated patients. These data suggest that there is an extremely low response rate in patients treated with alpha interferon. In addition to the low response rate, interferon therapy causes severe side effects such as insomnia, depression, nausea, vomiting, fever and fatigue. Another approved class of drugs for treating HBV infection is reverse transcriptase inhibitors exemplified by lamivudine, entecavir, and tenofovir. Although reverse transcriptase inhibitors have good antiviral activity, resistance can develop rapidly during treatment, there is cross-reactivity of resistance, and side effects such as kidney damage. There is also cross-reactivity between reverse transcriptase inhibitors for HBV and HIV. Furthermore, reverse transcriptase inhibitors are not known to lead to HBV clearance and, worse, discontinuation of the therapy is known to lead to a rebound effect occurs in most cases that can be life threatening.
Targeting assembly of the HBV capsid protein (CP), which has no human homolog, may be a powerful, general approach for developing anti-HBV therapeutics. It has been found that heteroaryldihydropyrimidines (HAPs) can enhance the rate and extent of CP assembly over a broad concentration range leading to aberrant particles, dominated by hexagonal arrays of CP. HAPs can also stabilize virus cores, preventing normal dissociation and release of the genome. Without being bound by theory, it is believed that the compounds described herein can disrupt HBV assembly, altering either the timing of formation of the capsid, the stability of the capsid, or the geometry of capsid formation, and interfering with viral infection. It is appreciated that enhancing the rate of CP aggregation and/or the rate for capsid assembly can deplete the concentration of CP, resulting in inhibition of non-structural activities mediated by CP.
In one illustrative embodiment of the invention, a compound having the formula
or a pharmaceutically acceptable salt thereof is described, wherein
Ar1 is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;
R1 is hydrogen or pro-drug forming group;
Ak is alkylene;
Z is

where X is CHN3, C═O, C═NR5, —C(O)N(RN)—, or NRN, where R5 is hydroxy or a derivative thereof or amino or a derivative thereof, and RN is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkyl-C(O), heteroalkyl-C(O), alkoxyl-C(O), alkynyl-C(O), alkylacylamino-C(O), and heteroalkylacylamino-C(O), each of which is optionally substituted;
R4 is alkyl, heteroalkyl, alkenyl, or alkynyl, each of which is optionally substituted;
Y is O, or HN;
RA represents from 0 to 3 substituents independently in each instance, halo or selected from the group consisting of alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted; and
RB represents from 0 to 3 substituents independently in each instance, halogen or selected from the group consisting of alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted.
In another illustrative embodiment, a compound having the formula
or a pharmaceutically acceptable salt thereof is described, wherein;
Ar2 is aryl or heteroaryl each of which is optionally substituted;
R1 is independently in each instance selected from the group consisting of hydrogen and pro-drug forming group;
R4 is alkyl, heteroalkyl, alkenyl, or alkynyl, each of which is optionally substituted;
Y is O, or HN;
R6 is in each instance independently selected from the group consisting of hydrogen and Ak-Z1, where Ak is alkylene, and Z1 is independently in each instance hydrogen or NR2R3; where R2 and R3 are independently in each instance hydrogen, or selected from the group consisting of alkyl, cycloalkyl, heteroalkyl and heterocycloalkyl, each of which is optionally substituted, or
R2 and R3 are taken together with the attached nitrogen to form

wherein X is CHN3, C═O, —C(O)N(RNa)—, C═NR5, or NRNa; where R5 is hydroxy or a derivative thereof or amino or a derivative thereof; and RNa is selected from the group consisting of hydrogen, and alkyl, alkenyl, alkynyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkyl-C(O), heteroalkyl-C(O), alkoxyl-C(O), alkynyl-C(O), alkylacylamino-C(O), and heteroalkylacylamino-C(O), each of which is optionally substituted;
Ak1 is (CH2)n, where n is 1 to 4;
RA represents from 0 to 3 substituents independently in each instance, halo or selected from the group consisting of alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted; and
RB represents from 0 to 3 substituents independently in each instance, halogen or selected from the group consisting of alkyl, heteroalkyl, aryl, heteroaryl, amino and derivatives thereof, and hydroxyl and derivatives thereof, each of which is optionally substituted.
In addition, various genera and subgenera of each of R1, R2, R3, R4, R5, R6, Ar1, Ar2, X, Ak, Ak1, RA, RB, and Z are described herein. It is to be understood that all possible combinations of the various genera and subgenera of each of R1, R2, R3, R4, R5, R6, Ar1, Ar2, X, Ak, Ak1, RA, RB, and Z described herein represent additional illustrative embodiments of compounds of the invention described herein. It is to be further understood that each of those additional illustrative embodiments of compounds may be used in any of the compositions, methods, and/or uses described herein.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with hepatitis B. It is to be understood that the compositions may include other component and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating patients with hepatitis B are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to a patient with hepatitis B. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with hepatitis B. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with hepatitis B are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with hepatitis B.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating hepatitis B, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of hepatitis B.